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Rare and low-frequency coding variants in CXCR2 and other genes are associated with hematological traits. Nat Genet 2014 Jun;46(6):629-34

Date

04/30/2014

Pubmed ID

24777453

Pubmed Central ID

PMC4050975

DOI

10.1038/ng.2962

Scopus ID

2-s2.0-84901684867 (requires institutional sign-in at Scopus site)   101 Citations

Abstract

Hematological traits are important clinical parameters. To test the effects of rare and low-frequency coding variants on hematological traits, we analyzed hemoglobin concentration, hematocrit levels, white blood cell (WBC) counts and platelet counts in 31,340 individuals genotyped on an exome array. We identified several missense variants in CXCR2 associated with reduced WBC count (gene-based P = 2.6 × 10(-13)). In a separate family-based resequencing study, we identified a CXCR2 frameshift mutation in a pedigree with congenital neutropenia that abolished ligand-induced CXCR2 signal transduction and chemotaxis. We also identified missense or splice-site variants in key hematopoiesis regulators (EPO, TFR2, HBB, TUBB1 and SH2B3) associated with blood cell traits. Finally, we were able to detect associations between a rare somatic JAK2 mutation (encoding p.Val617Phe) and platelet count (P = 3.9 × 10(-22)) as well as hemoglobin concentration (P = 0.002), hematocrit levels (P = 9.5 × 10(-7)) and WBC count (P = 3.1 × 10(-5)). In conclusion, exome arrays complement genome-wide association studies in identifying new variants that contribute to complex human traits.

Author List

Auer PL, Teumer A, Schick U, O'Shaughnessy A, Lo KS, Chami N, Carlson C, de Denus S, Dubé MP, Haessler J, Jackson RD, Kooperberg C, Perreault LP, Nauck M, Peters U, Rioux JD, Schmidt F, Turcot V, Völker U, Völzke H, Greinacher A, Hsu L, Tardif JC, Diaz GA, Reiner AP, Lettre G

Author

Paul L. Auer PhD Professor in the Institute for Health and Equity department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Adult
Aged
Chemotaxis
Exome
Female
Frameshift Mutation
Genome-Wide Association Study
Genotype
Hematocrit
Hematopoiesis
Hemoglobins
Humans
Janus Kinase 2
Leukocyte Count
Male
Middle Aged
Mutation, Missense
Neutropenia
Pedigree
Platelet Count
Receptors, Interleukin-8B